| Eligibility |
Inclusion Criteria:
A subject must fully meet all of the following criteria to be eligible for the study:
1. The subject has a pathologic diagnosis of non-small cell lung carcinoma that is
metastatic or unresectable.
2. Documented presence:
1. Group A: KIF5B/RET or related variant RET fusions.
2. Group B: any of the following aberrations
ii. NTRK fusion iii. MET overexpression, amplification, or mutation iv. AXL
overexpression, amplification, or mutation
3. Group C: ROS1 fusion
4. GROUP D: RET-fusion post-progression on selective RET inhibitor
3. The subject is = 18 years old on the day of consent.
4. Measurable Disease by RECIST1.1
5. The subject has a Karnofsky performance status of > 70%.
6. The subject has organ and marrow function and laboratory values as follows:
1. Absolute neutrophil count (ANC) = 1500/mm3 without colony stimulating factor
support
2. Platelets = 100,000/mm3 Hemoglobin = 9 g/dL
3. Bilirubin = 1.5 × the upper limit of normal (ULN). For subjects with known
Gilbert's . disease, bilirubin = 3.0 mg/dL
4. Serum creatinine = 1.5 × ULN or creatinine clearance (CrCl) = 30 mL/min. For
creatinine clearance estimation, the Cockcroft and Gault equation should be used:
Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72) Female:
Multiply above result by 0.85
5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
= 3.0 × ULN if no liver involvement, or = 5 × ULN with liver involvement
6. Urine protein/creatinine ratio (UPCR) = 1 mg/mg (113.2 mg/mmol) creatinine or
24-hr urine protein of < 1 g
7. Serum phosphorus, magnesium, and potassium = LLN after adequate supplementation
if necessary
8. The subject is capable of understanding and complying with the protocol
requirements and has signed the informed consent document. Sexually active
subjects (men and women) must agree to use medically accepted barrier methods of
contraception (eg, male or female condom) during the course of the study and for
4 months after the last dose of study drug(s), even if oral contraceptives are
also used. All subjects of reproductive potential must agree to use both a
barrier method and a second method of birth control. Women of childbearing
potential must have a negative pregnancy test at screening.
9. Women of childbearing potential include women who have experienced menarche and
who have not undergone successful surgical sterilization (hysterectomy, bilateral
tubal ligation, or bilateral oophorectomy) or are not postmenopausal.
10. Postmenopause is defined as amenorrhea = 12 consecutive months. Note:
women who have been amenorrheic for 12 or more months are still considered to be of
childbearing potential if the amenorrhea is possibly due to prior chemotherapy,
antiestrogens, ovarian suppression or any other reversible reason.
Exclusion Criteria:
1. Any type of systemic anticancer agent (including investigational) within 3 weeks of
first dose of study treatment, or within 5 half-lives of the agent whichever is
shorter. Subjects on LHRH or GnRH agonists may be maintained on these agents.
2. Prior treatment with cabozantinib
3. Radiation therapy for bone or brain metastasis within 2 weeks, any other external
radiation therapy within 4 weeks of first dose of study drug. Systemic treatment with
radionuclides within 4weeks. Subjects with clinically relevant ongoing complications
from prior radiation therapy are not eligible.
4. The subject has not recovered to baseline or CTCAE = Grade 1 from toxicity due to all
prior therapies except alopecia and other non-clinically significant AEs.
5. Known uncontrolled symptomatic brain metastases or cranial epidural disease; subjects
previously treated and on stable dose of corticosteroids and/or anticonvulsants for
>10 days, or not requiring such medications, are eligible. Baseline brain scans are
not required to confirm eligibility.
Radiation therapy for bone or brain metastases within 2 weeks before first dose of
study drug; or any other external radiation therapy or systemic treatment with
radionuclides within 4 weeks before first dose of study drug. Subjects with clinically
relevant ongoing complications from prior radiation therapy are not eligible
6. The subject requires concomitant treatment, in therapeutic doses, unless deemed
clinically unsafe to discontinue, with anticoagulants such as warfarin or
warfarin-related agents, unfractionated heparin, thrombin or Factor Xa inhibitors, or
antiplatelet agents (eg, clopidogrel). Low dose aspirin (= 100 mg/day), low-dose
warfarin (= 1 mg/day) are permitted. Both prophylactic and/or treatment dose low
molecular weight (fractionated) heparin (LMWH) are permitted and are the preferred
agents to administer.
7. The subject has experienced any of the following within 3 months before the first dose
of study treatment:
- clinically-significant hematemesis or gastrointestinal bleeding
- Clinically-significant hemoptysis of = 0.5 teaspoon (2.5ml) of red blood c. any
other signs indicative of pulmonary hemorrhage
8. The subject has radiographic evidence of cavitating pulmonary lesion(s)
9. The subject has tumor in contact with invading major blood vessels
10. The subject has any evidence of an endotracheal or endobronchial tumor within 28 days
before the first dose of cabozantinib.
11. The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
- Cardiovascular disorders including Congestive heart failure (CHF): New York Heart
Association (NYHA) Class III (moderate) or Class IV (severe) at the time of
screening
- Concurrent uncontrolled hypertension defined as sustained BP = 150 mm Hg
systolic, or = 90 mm Hg diastolic despite optimal antihypertensive treatment
(Note: If there is any BP measurement that is performed within the screening
period that is < 150 mm Hg systolic and <90 mm Hg diastolic, then BP does
not meet definition of sustained.)
---- Any congenital history of long QT syndrome.
- Any of the following within 6 months before the first dose of study
treatment:
- unstable angina pectoris
- clinically-significant cardiac arrhythmias
- stroke (including TIA, or other ischemic event) myocardial infarction
- thromboembolic event requiring therapeutic anticoagulation except if
anticoagulation is as stipulated in Exclusion Criterium #6. (Note:
subjects with a venous filter (e.g. vena cava filter) are not eligible
for this study)
- Gastrointestinal disorders particularly those associated with a high risk of
perforation or fistula formation including:
- Any of the following within 28 days before the first dose of study
treatmentF
- intra-abdominal tumor/metastases invading GI mucosa (malignant
abdominal ascites does not constitute mucosal invasion)
- active peptic ulcer disease,
- inflammatory bowel disease (including ulcerative colitis and Crohn's
disease), diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis
- malabsorption syndrome
- Any of the following within 6 months before the first dose of study
treatment:
- history of abdominal fistula
- gastrointestinal perforation
- bowel obstruction or gastric outlet obstruction
- intra-abdominal abscess. Note: Complete resolution of an
intra-abdominal abscess must be confirmed prior to initiating treatment
with cabozantinib even if the abscess occurred more that 6 months ago.
GI surgery (particularly when associated with delayed or incomplete
healing) within 28 days. Note: Complete healing following abdominal
surgery must be confirmed prior to initiating treatment with
cabozantinib even if surgery occurred more that 28 days ago.
- Other disorders associated with a high risk of fistula formation including PEG
tube placement within 3 months before the first dose of study therapy or
concurrent evidence of intraluminal tumor involving the trachea and esophagus.
- Other clinically significant disorders such as:
- active infection requiring systemic treatment within 28 days before the
first dose of study treatment
- serious non-healing wound/ulcer/bone fracture within 28 days before the
first dose of study treatment
- history of organ transplant
- concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days
before the first dose of study treatment
- Major surgery (eg, thoracotomy, removal or biopsy of brain metastasis)
within 3 months before Week 1 Day 1. Complete wound healing from major
surgery must have occurred 1 month before Week 1 Day 1 and from minor
surgery (eg, simple excision, tooth extraction) at least 10 days before Week
1 Day 1. Subjects with clinically relevant ongoing complications from prior
surgery are not eligible.
- history of major surgery as follows:
12. The subject is unable to swallow tablets
13. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >
500 ms 14 days before Week 1 Day 1
14. The subject is pregnant or breastfeeding.
15. The subject has a previously identified allergy or hypersensitivity to components of
the study treatment formulation.
16. The subject is unable or unwilling to abide by the study protocol or cooperate fully
with the investigator or designee.
17. Uncontrolled concurrent malignancy that would limit assessment of efficacy of
cabozantinib.
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